Topamax (topiramate) tablet, coated
Janssen Pharmaceuticals, Inc.

Janssen Pharmaceuticals, Inc.
Janssen Ortho, LLC
Janssen Pharmaceuticals, Inc.
Cilag AG
Topamax
topiramate
LACTOSE MONOHYDRATE
MICROCRYSTALLINE CELLULOSE
SODIUM STARCH GLYCOLATE TYPE A POTATO
MAGNESIUM STEARATE
WATER
CARNAUBA WAX
HYPROMELLOSE, UNSPECIFIED
TITANIUM DIOXIDE
POLYETHYLENE GLYCOL, UNSPECIFIED
POLYSORBATE 80
TOPIRAMATE
TOPIRAMATE
cream
OMN;25
Topamax
topiramate
LACTOSE MONOHYDRATE
MICROCRYSTALLINE CELLULOSE
SODIUM STARCH GLYCOLATE TYPE A POTATO
MAGNESIUM STEARATE
WATER
CARNAUBA WAX
HYPROMELLOSE, UNSPECIFIED
TITANIUM DIOXIDE
POLYETHYLENE GLYCOL, UNSPECIFIED
POLYSORBATE 80
TOPIRAMATE
TOPIRAMATE
light yellow
OMN;50
Topamax
topiramate
LACTOSE MONOHYDRATE
MICROCRYSTALLINE CELLULOSE
SODIUM STARCH GLYCOLATE TYPE A POTATO
MAGNESIUM STEARATE
WATER
CARNAUBA WAX
HYPROMELLOSE, UNSPECIFIED
TITANIUM DIOXIDE
POLYETHYLENE GLYCOL, UNSPECIFIED
POLYSORBATE 80
TOPIRAMATE
TOPIRAMATE
OMN;100
Topamax
topiramate
LACTOSE MONOHYDRATE
MICROCRYSTALLINE CELLULOSE
SODIUM STARCH GLYCOLATE TYPE A POTATO
MAGNESIUM STEARATE
WATER
CARNAUBA WAX
HYPROMELLOSE, UNSPECIFIED
TITANIUM DIOXIDE
POLYETHYLENE GLYCOL, UNSPECIFIED
POLYSORBATE 80
TOPIRAMATE
TOPIRAMATE
salmon
OMN;200
Topamax
topiramate
RAW SUGAR
POVIDONE, UNSPECIFIED
CELLULOSE ACETATE
GELATIN, UNSPECIFIED
SORBITAN MONOLAURATE
SODIUM LAURYL SULFATE
TITANIUM DIOXIDE
TOPIRAMATE
TOPIRAMATE
white and clear
TOP;15mg
Topamax
topiramate
RAW SUGAR
POVIDONE, UNSPECIFIED
CELLULOSE ACETATE
GELATIN, UNSPECIFIED
SORBITAN MONOLAURATE
SODIUM LAURYL SULFATE
TITANIUM DIOXIDE
TOPIRAMATE
TOPIRAMATE
white and clear
TOP;25mg
Warnings and Precautions ( 5.1, 5.4, 5.7, 5.9, 5.10, 5.13) 10/2022

1 INDICATIONS AND USAGE

TOPAMAX ® is indicated for:

  • Epilepsy: initial monotherapy for the treatment of partial-onset or primary generalized tonic-clonic seizures in patients 2 years of age and older ( 1.1); adjunctive therapy for the treatment of partial-onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome in patients 2 years of age and older ( 1.2)
  • Preventive treatment of migraine in patients 12 years of age and older ( 1.3)

1.1 Monotherapy Epilepsy

TOPAMAX ® is indicated as initial monotherapy for the treatment of partial-onset or primary generalized tonic-clonic seizures in patients 2 years of age and older.

1.2 Adjunctive Therapy Epilepsy

TOPAMAX ® is indicated as adjunctive therapy for the treatment of partial-onset seizures, primary generalized tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome in patients 2 years of age and older.

1.3 Migraine

TOPAMAX ® is indicated for the preventive treatment of migraine in patients 12 years of age and older.

2 DOSAGE AND ADMINISTRATION

TOPAMAX ® initial dose, titration, and recommended maintenance dose varies by indication and age group. See Full Prescribing Information for recommended dosage, and dosing considerations in patients with renal impairment, geriatric patients, and patients undergoing hemodialysis ( 2.1, 2.2, 2.3, 2.4, 2.5, 2.6)

2.1 Dosing in Monotherapy Epilepsy

Adults and Pediatric Patients 10 Years of Age and Older

The recommended dose for TOPAMAX ® monotherapy in adults and pediatric patients 10 years of age and older is 400 mg/day in two divided doses. The dose should be achieved by titration according to the following schedule (Table 1):

Table 1: Monotherapy Titration Schedule for Adults and Pediatric Patients 10 years and older
Morning Dose Evening Dose
Week 1 25 mg 25 mg
Week 2 50 mg 50 mg
Week 3 75 mg 75 mg
Week 4 100 mg 100 mg
Week 5 150 mg 150 mg
Week 6 200 mg 200 mg

Pediatric Patients 2 to 9 Years of Age

Dosing in patients 2 to 9 years of age is based on weight. During the titration period, the initial dose of TOPAMAX ® is 25 mg/day nightly for the first week. Based upon tolerability, the dosage can be increased to 50 mg/day (25 mg twice daily) in the second week. Dosage can be increased by 25–50 mg/day each subsequent week as tolerated. Titration to the minimum maintenance dose should be attempted over 5–7 weeks of the total titration period. Based upon tolerability and clinical response, additional titration to a higher dose (up to the maximum maintenance dose) can be attempted at 25–50 mg/day weekly increments. The total daily dose should not exceed the maximum maintenance dose for each range of body weight (Table 2).

Table 2: Monotherapy Target Total Daily Maintenance Dosing for Patients 2 to 9 Years of Age
Weight (kg) Total Daily Dose (mg/day) Administered in two equally divided doses
Minimum Maintenance Dose
Total Daily Dose (mg/day)

Maximum Maintenance Dose
Up to 11 150 250
12 – 22 200 300
23 – 31 200 350
32 – 38 250 350
Greater than 38 250 400

2.2 Dosing in Adjunctive Therapy Epilepsy

Adults (17 Years of Age and Older)

The recommended total daily dose of TOPAMAX ® as adjunctive therapy in adults with partial onset seizures or Lennox-Gastaut Syndrome is 200 to 400 mg/day in two divided doses, and 400 mg/day in two divided doses as adjunctive treatment in adults with primary generalized tonic-clonic seizures. TOPAMAX ® should be initiated at 25 to 50 mg/day, followed by titration to an effective dose in increments of 25 to 50 mg/day every week. Titrating in increments of 25 mg/day every week may delay the time to reach an effective dose. Doses above 400 mg/day have not been shown to improve responses in adults with partial-onset seizures.

Pediatric Patients 2 to 16 Years of Age

The recommended total daily dose of TOPAMAX ® as adjunctive therapy for pediatric patients 2 to 16 years of age with partial-onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome is approximately 5 to 9 mg/kg/day in two divided doses. Titration should begin at 25 mg/day (or less, based on a range of 1 to 3 mg/kg/day) nightly for the first week. The dosage should then be increased at 1- or 2-week intervals by increments of 1 to 3 mg/kg/day (administered in two divided doses), to achieve optimal clinical response. Dose titration should be guided by clinical outcome. The total daily dose should not exceed 400 mg/day.

2.3 Dosing for the Preventive Treatment of Migraine

The recommended total daily dose of TOPAMAX ® as treatment for patients 12 years of age and older for the preventive treatment of migraine is 100 mg/day administered in two divided doses (Table 3). The recommended titration rate for TOPAMAX ® for the preventive treatment of migraine is as follows:

Table 3: Preventive Treatment of Migraine Titration Schedule for Patients 12 Years of Age and Older
Morning Dose Evening Dose
Week 1 None 25 mg
Week 2 25 mg 25 mg
Week 3 25 mg 50 mg
Week 4 50 mg 50 mg

Dose and titration rate should be guided by clinical outcome. If required, longer intervals between dose adjustments can be used.

2.4 Administration Information

TOPAMAX ® can be taken without regard to meals.

TOPAMAX ® Tablets

Because of the bitter taste, tablets should not be broken.

TOPAMAX ® Sprinkle Capsules

TOPAMAX ® Sprinkle Capsules may be swallowed whole or may be administered by carefully opening the capsule and sprinkling the entire contents on a small amount (teaspoon) of soft food. This drug/food mixture should be swallowed immediately and not chewed. It should not be stored for future use.

2.5 Dosing in Patients with Renal Impairment

In patients with renal impairment (creatinine clearance less than 70 mL/min/1.73 m 2), one-half of the usual adult dose of TOPAMAX ® is recommended [see Use in Specific Populations (8.5, 8.6), Clinical Pharmacology (12.3)] .

2.6 Dosing in Patients Undergoing Hemodialysis

To avoid rapid drops in topiramate plasma concentration during hemodialysis, a supplemental dose of TOPAMAX ® may be required. The actual adjustment should take into account 1) the duration of dialysis period, 2) the clearance rate of the dialysis system being used, and 3) the effective renal clearance of topiramate in the patient being dialyzed [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)] .

3 DOSAGE FORMS AND STRENGTHS

TOPAMAX ® Tablets are available as debossed, coated, round tablets in the following strengths and colors:

25 mg cream (debossed "OMN" on one side; "25" on the other)

50 mg light-yellow (debossed "OMN" on one side; "50" on the other)

100 mg yellow (debossed "OMN" on one side; "100" on the other)

200 mg salmon (debossed "OMN" on one side; "200" on the other)

TOPAMAX ® Sprinkle Capsules contain small, white to off-white spheres. The gelatin capsules are white and clear.

They are marked as follows:

15 mg capsule with "TOP" and "15 mg" on the side

25 mg capsule with "TOP" and "25 mg" on the side

  • Tablets: 25 mg, 50 mg, 100 mg, and 200 mg ( 3)
  • Sprinkle Capsules: 15 mg and 25 mg ( 3)

4 CONTRAINDICATIONS

None.

None ( 4)

5 WARNINGS AND PRECAUTIONS

  • Acute myopia and secondary angle closure glaucoma: can lead to permanent visual loss; discontinue TOPAMAX ® as soon as possible ( 5.1)
  • Visual field defects: consider discontinuation of TOPAMAX ® ( 5.2)
  • Oligohidrosis and hyperthermia: monitor decreased sweating and increased body temperature, especially in pediatric patients ( 5.3)
  • Metabolic acidosis: baseline and periodic measurement of serum bicarbonate is recommended; consider dose reduction or discontinuation of TOPAMAX ® if clinically appropriate ( 5.4)
  • Suicidal behavior and ideation: antiepileptic drugs increase the risk of suicidal behavior or ideation ( 5.5)
  • Cognitive/neuropsychiatric adverse reactions: use caution when operating machinery including cars; depression and mood problems may occur ( 5.6)
  • Fetal Toxicity: use during pregnancy can cause major congenital malformations, including but not limited to cleft lip and/or palate, and being small for gestational age ( 5.7)
  • Withdrawal of AEDs: withdraw TOPAMAX ® gradually ( 5.8)
  • Decrease in Bone Mineral Density: has been shown to decrease bone mineral density and bone mineral content in pediatric patients ( 5.9)
  • Negative effects on growth (height and weight): may slow height increase and weight gain; carefully monitor children receiving prolonged therapy ( 5.10)
  • Serious skin reactions: If SJS or TEN is suspected, discontinue TOPAMAX ® ( 5.11)
  • Hyperammonemia/encephalopathy: measure ammonia if encephalopathic symptoms occur ( 5.12)
  • Kidney stones: avoid use with other carbonic anhydrase inhibitors, drugs causing metabolic acidosis, or in patients on a ketogenic diet ( 5.13)
  • Hypothermia has been reported with and without hyperammonemia during topiramate treatment with concomitant valproic acid use ( 5.14)

5.1 Acute Myopia and Secondary Angle Closure Glaucoma Syndrome

A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving TOPAMAX ®. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include some or all of the following: myopia, mydriasis, anterior chamber shallowing, ocular hyperemia (redness), choroidal detachments, retinal pigment epithelial detachments, macular striae, and increased intraocular pressure. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur within 1 month of initiating TOPAMAX ® therapy. In contrast to primary narrow angle glaucoma, which is rare under 40 years of age, secondary angle closure glaucoma associated with topiramate has been reported in pediatric patients as well as adults. The primary treatment to reverse symptoms is discontinuation of TOPAMAX ® as rapidly as possible, according to the judgment of the treating physician. Other measures, in conjunction with discontinuation of TOPAMAX ®, may be helpful.

Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent vision loss.

5.2 Visual Field Defects

Visual field defects (independent of elevated intraocular pressure) have been reported in clinical trials and in postmarketing experience in patients receiving topiramate. In clinical trials, most of these events were reversible after topiramate discontinuation. If visual problems occur at any time during topiramate treatment, consideration should be given to discontinuing the drug.

5.3 Oligohidrosis and Hyperthermia

Oligohidrosis (decreased sweating), infrequently resulting in hospitalization, has been reported in association with TOPAMAX ® use. Decreased sweating and an elevation in body temperature above normal characterized these cases. Some of the cases were reported after exposure to elevated environmental temperatures.

The majority of the reports have been in pediatric patients. Patients (especially pediatric patients) treated with TOPAMAX ® should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather. Caution should be used when TOPAMAX ® is given with other drugs that predispose patients to heat-related disorders; these drugs include, but are not limited to, other carbonic anhydrase inhibitors and drugs with anticholinergic activity.

5.4 Metabolic Acidosis

TOPAMAX ® can cause hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis). This metabolic acidosis is caused by renal bicarbonate loss due to carbonic anhydrase inhibition by TOPAMAX ®. TOPAMAX ®-induced metabolic acidosis can occur at any time during treatment. Bicarbonate decrements are usually mild-moderate (average decrease of 4 mEq/L at daily doses of 400 mg in adults and at approximately 6 mg/kg/day in pediatric patients); rarely, patients can experience severe decrements to values below 10 mEq/L. Conditions or therapies that predispose patients to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, ketogenic diet, or specific drugs) may be additive to the bicarbonate lowering effects of TOPAMAX ®.

Metabolic acidosis was commonly observed in adult and pediatric patients treated with TOPAMAX ® in clinical trials. The incidence of decreased serum bicarbonate in pediatric trials, for adjunctive treatment of Lennox-Gastaut syndrome or refractory partial-onset seizures was as high as 67% for TOPAMAX ® (at approximately 6 mg/kg/day), and 10% for placebo. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value < 17 mEq/L and ≥5 mEq/L decrease from pretreatment) in these trials was up to 11%, compared to ≤ 2% for placebo.

Manifestations of acute or chronic metabolic acidosis may include hyperventilation, nonspecific symptoms such as fatigue and anorexia, or more severe sequelae including cardiac arrhythmias or stupor. Chronic, untreated metabolic acidosis may increase the risk for nephrolithiasis or nephrocalcinosis, and may also result in osteomalacia (referred to as rickets in pediatric patients) and/or osteoporosis with an increased risk for fractures [see Warnings and Precautions (5.9, 5.13)] . A one-year, active-controlled study of pediatric patients treated with TOPAMAX ® demonstrated that TOPAMAX ® decreased lumbar spine bone mineral density and that this lumbar spine bone mineral density decrease was correlated (using change from baseline for lumbar spine Z score at final visit versus lowest post-treatment serum bicarbonate) with decreased serum bicarbonate, a reflection of metabolic acidosis [see Warnings and Precautions (5.9), Use in Specific Populations (8.4)] . Chronic metabolic acidosis in pediatric patients may also reduce growth rates, which may decrease the maximal height achieved. Long-term, open-label treatment of pediatric patients 1 to 24 months old with intractable partial epilepsy, for up to 1 year, showed reductions from baseline in length, weight, and head circumference compared to age and sex-matched normative data, although these patients with epilepsy are likely to have different growth rates than normal 1 to 24 month old pediatrics. Reductions in length and weight were correlated to the degree of acidosis [see Use in Specific Populations (8.4)] . TOPAMAX ® treatment that causes metabolic acidosis during pregnancy can possibly produce adverse effects on the fetus and might also cause metabolic acidosis in the neonate from possible transfer of topiramate to the fetus [see Warnings and Precautions (5.7), Use in Specific Populations (8.1)] .

Measurement of Serum Bicarbonate in Epilepsy and Migraine Patients

Measurement of baseline and periodic serum bicarbonate during topiramate treatment is recommended. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing TOPAMAX ® (using dose tapering). If the decision is made to continue patients on TOPAMAX ® in the face of persistent acidosis, alkali treatment should be considered.

5.5 Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including TOPAMAX ®, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.

Table 4 shows absolute and relative risk by indication for all evaluated AEDs.

Table 4: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis
Indication Placebo Patients with Events per 1000 Patients Drug Patients with Events per 1000 Patients Relative Risk:
Incidence of Events in Drug Patients/Incidence in Placebo Patients
Risk Difference:
Additional Drug Patients with Events per 1000 Patients
Epilepsy 1.0 3.4 3.5 2.4
Psychiatric 5.7 8.5 1.5 2.9
Other 1.0 1.8 1.9 0.9
Total 2.4 4.3 1.8 1.9

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing TOPAMAX ® or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

5.6 Cognitive/Neuropsychiatric Adverse Reactions

TOPAMAX ® can cause cognitive/neuropsychiatric adverse reactions. The most frequent of these can be classified into three general categories: 1) Cognitive-related dysfunction (e.g., confusion, psychomotor slowing, difficulty with concentration/attention, difficulty with memory, speech or language problems, particularly word-finding difficulties); 2) Psychiatric/behavioral disturbances (e.g., depression or mood problems); and 3) Somnolence or fatigue.

Adult Patients

Cognitive-Related Dysfunction

Rapid titration rate and higher initial dose were associated with higher incidences of cognitive-related dysfunction.

In adult epilepsy adjunctive controlled trials, which used rapid titration (100–200 mg/day weekly increments), and target TOPAMAX ® doses of 200 mg – 1000 mg/day, 56% of patients in the 800 mg/day and 1000 mg/day dose groups experienced cognitive-related dysfunction compared to approximately 42% of patients in the 200–400 mg/day groups and 14% for placebo. In this rapid titration regimen, these dose-related adverse reactions began in the titration or in the maintenance phase, and in some patients these events began during titration and persisted into the maintenance phase.

In the monotherapy epilepsy controlled trial, the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for TOPAMAX ® 50 mg/day and 26% for 400 mg/day.

In the 6-month controlled trials for the preventive treatment of migraine, which used a slower titration regimen (25 mg/day weekly increments), the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for TOPAMAX ® 50 mg/day, 22% for 100 mg/day (the recommended dose), 28% for 200 mg/day, and 10% for placebo. Cognitive adverse reactions most commonly developed during titration and sometimes persisted after completion of titration.

Psychiatric/Behavioral Disturbances

Psychiatric/behavioral disturbances (e.g., depression, mood) were dose-related for both the adjunctive epilepsy and migraine populations [see Warnings and Precautions (5.5)].

Somnolence/Fatigue

Somnolence and fatigue were the adverse reactions most frequently reported during clinical trials of TOPAMAX ® for adjunctive epilepsy. For the adjunctive epilepsy population, the incidence of fatigue, appeared dose related. For the monotherapy epilepsy population, the incidence of somnolence was dose-related. For the migraine population, the incidences of both fatigue and somnolence were dose-related and more common in the titration phase.

Pediatric Patients

In pediatric epilepsy trials (adjunctive and monotherapy), the incidence of cognitive/neuropsychiatric adverse reactions was generally lower than that observed in adults. These reactions included psychomotor slowing, difficulty with concentration/attention, speech disorders/related speech problems, and language problems. The most frequently reported cognitive/neuropsychiatric reactions in pediatric epilepsy patients during adjunctive therapy double-blind studies were somnolence and fatigue. The most frequently reported cognitive/neuropsychiatric reactions in pediatric epilepsy patients in the 50 mg/day and 400 mg/day groups during the monotherapy double-blind study were headache, dizziness, anorexia, and somnolence.

In pediatric migraine patients, the incidence of cognitive/neuropsychiatric adverse reactions was increased in TOPAMAX ®-treated patients compared to placebo.

The risk for cognitive/neuropsychiatric adverse reactions was dose-dependent, and was greatest at the highest dose (200 mg). This risk for cognitive/neuropsychiatric adverse reactions was also greater in younger patients (6 to 11 years of age) than in older patients (12 to 17 years of age).

The most common cognitive/neuropsychiatric adverse reaction in these trials was difficulty with concentration/attention. Cognitive adverse reactions most commonly developed during titration and sometimes persisted for various durations after completion of titration.

The Cambridge Neuropsychological Test Automated Battery (CANTAB) was administered to adolescents (12 to 17 years) to assess the effects of topiramate on cognitive function at baseline and at the end of the Study 13 [see Clinical Studies (14.3)] . Mean change from baseline in certain CANTAB tests suggests that topiramate treatment may result in psychomotor slowing and decreased verbal fluency.

5.7 Fetal Toxicity

TOPAMAX ® can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have an increased risk of major congenital malformations, including but not limited to cleft lip and/or cleft palate (oral clefts), and of being small for gestational age (SGA). When multiple species of pregnant animals received topiramate at clinically relevant doses, structural malformations, including craniofacial defects, and reduced fetal weights occurred in offspring [see Use in Specific Populations (8.1)] .

Consider the benefits and the risks of TOPAMAX ® when administering this drug in women of childbearing potential, particularly when TOPAMAX ® is considered for a condition not usually associated with permanent injury or death [see Use in Specific Populations (8.1), Patient Counseling Information (17)] . TOPAMAX ® should be used during pregnancy only if the potential benefit outweighs the potential risk. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)] .

5.8 Withdrawal of Antiepileptic Drugs

In patients with or without a history of seizures or epilepsy, antiepileptic drugs, including TOPAMAX ®, should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency [see Clinical Studies (14)] . In situations where rapid withdrawal of TOPAMAX ® is medically required, appropriate monitoring is recommended.

5.9 Decrease in Bone Mineral Density

Results of a one-year active-controlled study in pediatric patients (N=63) demonstrated negative effects of TOPAMAX ® monotherapy on bone mineral acquisition via statistically significant decreases in bone mineral density (BMD) measured in lumbar spine and in total body less head [see Use in Specific Populations (8.4)] . Twenty-one percent of TOPAMAX ®-treated patients experienced clinically important reductions in BMD (Z score change from baseline of –0.5 or greater) compared to 0 patients in the control group. Although decreases in BMD occurred across all pediatric age subgroups, patients 6 to 9 years of age were most commonly affected. The sample size and study duration were too small to determine if fracture risk is increased. Decreased BMD in the lumbar spine was correlated with decreased serum bicarbonate, which commonly occurs with TOPAMAX treatment and reflects metabolic acidosis, a known cause of increased bone resorption [see Warnings and Precautions (5.4)] . Although small decreases in some markers of bone metabolism (e.g., serum alkaline phosphatase, calcium, phosphorus, and 1,25-dihydroxyvitamin D) occurred in TOPAMAX ®-treated patients, more significant decreases in serum parathyroid hormone and 25-hydroxyvitamin D, hormones involved in bone metabolism, were observed, along with an increased excretion of urinary calcium .

5.10 Negative Effects on Growth (Height and Weight)

Results of a one-year active-controlled study of pediatric patients (N=63) demonstrated negative effects of TOPAMAX ® monotherapy on growth (i.e., height and weight) [see Use in Specific Populations (8.4)] . Although continued growth was observed in both treatment groups, the TOPAMAX ® group showed statistically significant reductions in mean annual change from baseline in body weight compared to the control group. A similar trend of attenuation in height velocity and height change from baseline was also observed in the TOPAMAX ® group compared to the control group. Negative effects on weight and height were seen across all TOPAMAX ® age subgroups. Growth (height and weight) of children receiving prolonged TOPAMAX ® therapy should be carefully monitored.

5.11 Serious Skin Reactions

Serious skin reactions (Stevens-Johnson Syndrome [SJS] and Toxic Epidermal Necrolysis [TEN]) have been reported in patients receiving topiramate. TOPAMAX should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. Inform patients about the signs of serious skin reactions.

5.12 Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid Use)

Topiramate treatment can cause hyperammonemia with or without encephalopathy [see Adverse Reactions (6.2)] . The risk for hyperammonemia with topiramate appears dose-related. Hyperammonemia has been reported more frequently when topiramate is used concomitantly with valproic acid. Postmarketing cases of hyperammonemia with or without encephalopathy have been reported with topiramate and valproic acid in patients who previously tolerated either drug alone [see Drug Interactions (7.1)] .

Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy and/or vomiting. In most cases, hyperammonemic encephalopathy abated with discontinuation of treatment.

The incidence of hyperammonemia in pediatric patients 12 to 17 years of age in the preventive treatment of migraine trials was 26% in patients taking TOPAMAX ® monotherapy at 100 mg/day, and 14% in patients taking TOPAMAX ® at 50 mg/day, compared to 9% in patients taking placebo. There was also an increased incidence of markedly increased hyperammonemia at the 100 mg dose.

Dose-related hyperammonemia was also seen in pediatric patients 1 to 24 months of age treated with TOPAMAX ® and concomitant valproic acid for partial-onset epilepsy and this was not due to a pharmacokinetic interaction.

In some patients, hyperammonemia can be asymptomatic.

Monitoring for Hyperammonemia

Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, topiramate treatment or an interaction of concomitant topiramate and valproic acid treatment may exacerbate existing defects or unmask deficiencies in susceptible persons.

In patients who develop unexplained lethargy, vomiting or changes in mental status associated with any topiramate treatment, hyperammonemic encephalopathy should be considered and an ammonia level should be measured.

5.13 Kidney Stones

TOPAMAX ® increases the risk of kidney stones. During adjunctive epilepsy trials, the risk for kidney stones in TOPAMAX ®-treated adults was 1.5%, an incidence about 2 to 4 times greater than expected in a similar, untreated population. As in the general population, the incidence of stone formation among TOPAMAX ®-treated patients was higher in men. Kidney stones have also been reported in pediatric patients taking TOPAMAX ® for epilepsy or migraine. During long-term (up to 1 year) TOPAMAX ® treatment in an open-label extension study of 284 pediatric patients 1–24 months old with epilepsy, 7% developed kidney or bladder stones. TOPAMAX ® is not approved for treatment of epilepsy in pediatric patients less than 2 years old [see Use in Specific Populations (8.4)].

TOPAMAX ® is a carbonic anhydrase inhibitor. Carbonic anhydrase inhibitors can promote stone formation by reducing urinary citrate excretion and by increasing urinary pH [see Warnings and Precautions (5.4)] . The concomitant use of TOPAMAX ® with any other drug producing metabolic acidosis, or potentially in patients on a ketogenic diet, may create a physiological environment that increases the risk of kidney stone formation, and should therefore be avoided.

Increased fluid intake increases the urinary output, lowering the concentration of substances involved in stone formation. Hydration is recommended to reduce new stone formation.

An increase in urinary calcium and a marked decrease in urinary citrate was observed in TOPAMAX-treated pediatric patients in a one-year active-controlled study [see Use in Specific Populations (8.4)] . This increased ratio of urinary calcium/citrate increases the risk of kidney stones and/or nephrocalcinosis.

5.14 Hypothermia with Concomitant Valproic Acid Use

Hypothermia, defined as a drop in body core temperature to <35°C (95°F), has been reported in association with topiramate use with concomitant valproic acid both in conjunction with hyperammonemia and in the absence of hyperammonemia. This adverse reaction in patients using concomitant topiramate and valproate can occur after starting topiramate treatment or after increasing the daily dose of topiramate [see Drug Interactions (7.1)] . Consideration should be given to stopping TOPAMAX ® or valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels.

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed in more detail in other sections of the labeling:

The data described in the following sections were obtained using TOPAMAX ® Tablets.

Epilepsy: Most common (≥10% more frequent than placebo or low-dose TOPAMAX ®) adverse reactions in adult and pediatric patients were: paresthesia, anorexia, weight loss, speech disorders/related speech problems, fatigue, dizziness, somnolence, nervousness, psychomotor slowing, abnormal vision and fever ( 6.1)

Migraine: Most common (≥5% more frequent than placebo) adverse reactions in adult and pediatric patients were: paresthesia, anorexia, weight loss, difficulty with memory, taste perversion, diarrhea, hypoesthesia, nausea, abdominal pain and upper respiratory tract infection ( 6.1)


To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals, Inc. at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the incidence of adverse reactions observed in the clinical trials of a drug cannot be directly compared to the incidence of adverse reactions in the clinical trials of another drug, and may not reflect the incidence of adverse reactions observed in practice.

Monotherapy Epilepsy

Adults 16 Years of Age and Older

The most common adverse reactions in the controlled clinical trial (Study 1) that occurred in adults in the 400 mg/day TOPAMAX ® group and at an incidence higher (≥ 10 %) than in the 50 mg/day group were: paresthesia, weight loss and anorexia (see Table 5).

Approximately 21% of the 159 adult patients in the 400 mg/day group who received TOPAMAX ® as monotherapy in Study 1 discontinued therapy due to adverse reactions. The most common (≥ 2% more frequent than low-dose 50 mg/day TOPAMAX ®) adverse reactions causing discontinuation were difficulty with memory, fatigue, asthenia, insomnia, somnolence, and paresthesia.

Pediatric Patients 6 to 15 Years of Age

The most common adverse reactions in the controlled clinical trial (Study 1) that occurred in pediatric patients in the 400 mg/day TOPAMAX ® group and at an incidence higher (≥10%) than in the 50 mg/day group were fever and weight loss (see Table 5).

Approximately 14% of the 77 pediatric patients in the 400 mg/day group who received TOPAMAX ® as monotherapy in the controlled clinical trial discontinued therapy due to adverse reactions. The most common (≥2% more frequent than low-dose 50 mg/day TOPAMAX ®) adverse reactions resulting in discontinuation were difficulty with concentration/attention, fever, flushing, and confusion.

Table 5 presents the incidence of adverse reactions occurring in at least 3% of adult and pediatric patients treated with 400 mg/day TOPAMAX ® and occurring with greater incidence than 50 mg/day TOPAMAX ®.

Table 5: Adverse Reactions in the High Dose Group As Compared to the Low Dose Group, in Monotherapy Epilepsy Trial (Study 1) in Adult and Pediatric Patients
Age Group
Pediatric
(6 to 15 Years)
Adult
(Age ≥16 Years)
TOPAMAX ® Daily Dosage Group (mg/day)
50 400 50 400
Body System (N=74) (N=77) (N=160) (N=159)
  Adverse Reaction % % % %
Body as a Whole - General Disorders
  Asthenia 0 3 4 6
  Fever 1 12
  Leg pain 2 3
Central & Peripheral Nervous System Disorders
  Paresthesia 3 12 21 40
  Dizziness 13 14
  Ataxia 3 4
  Hypoesthesia 4 5
  Hypertonia 0 3
  Involuntary muscle contractions 0 3
  Vertigo 0 3
Gastro-Intestinal System Disorders
  Constipation 1 4
  Diarrhea 8 9
  Gastritis 0 3
  Dry mouth 1 3
Liver and Biliary System Disorders
  Increase in Gamma-GT 1 3
Metabolic and Nutritional Disorders
  Weight loss 7 17 6 17
Platelet, Bleeding & Clotting Disorders
  Epistaxis 0 4
Psychiatric Disorders
  Anorexia 4 14
  Anxiety 4 6
  Cognitive problems 1 6 1 4
  Confusion 0 3
  Depression 0 3 7 9
  Difficulty with concentration or attention 7 10 7 8
  Difficulty with memory 1 3 6 11
  Insomnia 8 9
  Decrease in libido 0 3
  Mood problems 1 8 2 5
  Personality disorder (behavior problems) 0 3
  Psychomotor slowing 3 5
  Somnolence 10 15
Red Blood Cell Disorders
  Anemia 1 3
Reproductive Disorders, Female
  Intermenstrual bleeding 0 3
  Vaginal hemorrhage 0 3
Resistance Mechanism Disorders
  Infection 3 8 2 3
  Viral infection 3 6 6 8
Respiratory System Disorders
  Bronchitis 1 5 3 4
  Upper respiratory tract infection 16 18
  Rhinitis 5 6 2 4
  Sinusitis 1 4
Skin and Appendages Disorders
  Alopecia 1 4 3 4
  Pruritus 1 4
  Rash 3 4 1 4
  Acne 2 3
Special Senses Other, Disorders
  Taste perversion 3 5
Urinary System Disorders
  Cystitis 1 3
  Micturition frequency 0 3
  Renal calculus 0 3
  Urinary incontinence 1 3
Vascular (Extracardiac) Disorders
  Flushing 0 5

Adjunctive Therapy Epilepsy

Adults 16 Years of Age and Older

In pooled controlled clinical trials in adults with partial-onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, 183 patients received adjunctive therapy with TOPAMAX ® at dosages of 200 to 400 mg/day (recommended dosage range) and 291 patients received placebo. Patients in these trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to TOPAMAX ® or placebo.

The most common adverse reactions in the controlled clinical trial that occurred in adult patients in the 200–400 mg/day TOPAMAX ® group with an incidence higher (≥ 10 %) than in the placebo group were: dizziness, speech disorders/related speech problems, somnolence, nervousness, psychomotor slowing, and vision abnormal (Table 6).

Table 6 presents the incidence of adverse reactions occurring in at least 3% of adult patients treated with 200 to 400 mg/day TOPAMAX ® and was greater than placebo incidence. The incidence of some adverse reactions (e.g., fatigue, dizziness, paresthesia, language problems, psychomotor slowing, depression, difficulty with concentration/attention, mood problems) was dose-related and much greater at higher than recommended TOPAMAX ® dosing (i.e., 600 mg – 1000 mg daily) compared to the incidence of these adverse reactions at the recommended dosing (200 mg to 400 mg daily) range.

Table 6: Most Common Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Epilepsy Trials in Adults Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to TOPAMAX ® or placebo.
Body System
  Adverse Reaction
Placebo
(N=291)
TOPAMAX ®
Dosage (mg/day)
200–400
(N=183)
Body as a Whole-General Disorders
  Fatigue 13 15
  Asthenia 1 6
  Back pain 4 5
  Chest pain 3 4
  Influenza-like symptoms 2 3
Central & Peripheral Nervous System Disorders
  Dizziness 15 25
  Ataxia 7 16
  Speech disorders/Related speech problems 2 13
  Paresthesia 4 11
  Nystagmus 7 10
  Tremor 6 9
  Language problems 1 6
  Coordination abnormal 2 4
  Gait abnormal 1 3
Gastro-Intestinal System Disorders
  Nausea 8 10
  Dyspepsia 6 7
  Abdominal pain 4 6
  Constipation 2 4
Metabolic and Nutritional Disorders
  Weight loss 3 9
Psychiatric Disorders
  Somnolence 12 29
  Nervousness 6 16
  Psychomotor slowing 2 13
  Difficulty with memory 3 12
  Confusion 5 11
  Anorexia 4 10
  Difficulty with concentration/attention 2 6
  Mood problems 2 4
  Agitation 2 3
  Aggressive reaction 2 3
  Emotional lability 1 3
  Cognitive problems 1 3
Reproductive Disorders
  Breast pain 2 4
Respiratory System Disorders
  Rhinitis 6 7
  Pharyngitis 2 6
  Sinusitis 4 5
Vision Disorders
  Vision abnormal 2 13
  Diplopia 5 10

In controlled clinical trials in adults, 11% of patients receiving TOPAMAX ® 200 to 400 mg/day as adjunctive therapy discontinued due to adverse reactions. This rate appeared to increase at dosages above 400 mg/day. Adverse reactions associated with discontinuing TOPAMAX ® included somnolence, dizziness, anxiety, difficulty with concentration or attention, fatigue and paresthesia.

Pediatric Patients 2 to 15 Years of Age

In pooled, controlled clinical trials in pediatric patients (2 to 15 years of age) with partial-onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, 98 patients received adjunctive therapy with TOPAMAX ® at dosages of 5 to 9 mg/kg/day (recommended dose range) and 101 patients received placebo.

The most common adverse reactions in the controlled clinical trial that occurred in pediatric patients in the 5 mg to 9 mg/kg/day TOPAMAX ® group with an incidence higher (≥ 10 %) than in the placebo group were: fatigue and somnolence (Table 7).

Table 7 presents the incidence of adverse reactions that occurred in at least 3% of pediatric patients 2 to 15 years of age receiving 5 mg to 9 mg/kg/day (recommended dose range) of TOPAMAX® and was greater than placebo incidence.

Table 7: Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Epilepsy Trials in Pediatric Patients 2 to 15 Years of Age Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to TOPAMAX ® or placebo. , Values represent the percentage of patients reporting a given adverse reaction. Patients may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category.
Body System/
Adverse Reaction
Placebo
(N=101)
%
TOPAMAX ®
(N=98)
%
Body as a Whole - General Disorders
  Fatigue 5 16
  Injury 13 14
Central & Peripheral Nervous System Disorders
  Gait abnormal 5 8
  Ataxia 2 6
  Hyperkinesia 4 5
  Dizziness 2 4
  Speech disorders/Related speech problems 2 4
Gastro-Intestinal System Disorders
  Nausea 5 6
  Saliva increased 4 6
  Constipation 4 5
  Gastroenteritis 2 3
Metabolic and Nutritional Disorders
  Weight loss 1 9
Platelet, Bleeding, & Clotting Disorders
  Purpura 4 8
  Epistaxis 1 4
Psychiatric Disorders
  Somnolence 16 26
  Anorexia 15 24
  Nervousness 7 14
  Personality disorder (behavior problems) 9 11
  Difficulty with concentration/attention 2 10
  Aggressive reaction 4 9
  Insomnia 7 8
  Difficulty with memory 0 5
  Confusion 3 4
  Psychomotor slowing 2 3
Resistance Mechanism Disorders
  Infection viral 3 7
Respiratory System Disorders
  Pneumonia 1 5
Skin and Appendages Disorders
  Skin disorder 2 3
Urinary System Disorders
  Urinary incontinence 2 4

None of the pediatric patients who received TOPAMAX ® adjunctive therapy at 5 to 9 mg/kg/day in controlled clinical trials discontinued due to adverse reactions.

Migraine

Adults

In the four multicenter, randomized, double-blind, placebo-controlled, parallel group migraine clinical trials for the preventive treatment of migraine (which included 35 pediatric patients 12 to 15 years of age), most adverse reactions occurred more frequently during the titration period than during the maintenance period.

The most common adverse reactions with TOPAMAX ® 100 mg in the clinical trials for the preventive treatment of migraine of predominantly adults that were seen at an incidence higher (≥ 5 %) than in the placebo group were: paresthesia, anorexia, weight loss, taste perversion, diarrhea, difficulty with memory, hypoesthesia, and nausea (see Table 8).

Table 8 includes those adverse reactions that occurred in the placebo-controlled trials where the incidence in any TOPAMAX ® treatment group was at least 3% and was greater than that for placebo patients. The incidence of some adverse reactions (e.g., fatigue, dizziness, somnolence, difficulty with memory, difficulty with concentration/attention) was dose-related and greater at higher than recommended TOPAMAX ® dosing (200 mg daily) compared to the incidence of these adverse reactions at the recommended dosing (100 mg daily).

Table 8: Adverse Reactions in Pooled, Placebo-Controlled, Migraine Trials in Adults Includes 35 adolescent patients age 12 to 15 years. , Values represent the percentage of patients reporting a given adverse reaction. Patients may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category.
TOPAMAX ® Dosage (mg/day)
Body System/
  Adverse Reaction
Placebo
(N=445)
%
50
(N=235)
%
100
(N=386)
%
Body as a Whole-General Disorders
  Fatigue 11 14 15
  Injury 7 9 6
Central & Peripheral Nervous System Disorders
  Paresthesia 6 35 51
  Dizziness 10 8 9
  Hypoesthesia 2 6 7
  Language problems 2 7 6
Gastro-Intestinal System Disorders
  Nausea 8 9 13
  Diarrhea 4 9 11
  Abdominal pain 5 6 6
  Dyspepsia 3 4 5
  Dry mouth 2 2 3
  Gastroenteritis 1 3 3
Metabolic and Nutritional Disorders
  Weight loss 1 6 9
Musculoskeletal System Disorders
  Arthralgia 2 7 3
Psychiatric Disorders
  Anorexia 6 9 15
  Somnolence 5 8 7
  Difficulty with memory 2 7 7
  Insomnia 5 6 7
  Difficulty with concentration/attention 2 3 6
  Mood problems 2 3 6
  Anxiety 3 4 5
  Depression 4 3 4
  Nervousness 2 4 4
  Confusion 2 2 3
  Psychomotor slowing 1 3 2
Reproductive Disorders, Female
  Menstrual disorder 2 3 2
Reproductive Disorders, Male
  Ejaculation premature 0 3 0
Resistance Mechanism Disorders
  Viral infection 3 4 4
Respiratory System Disorders
  Upper respiratory tract infection 12 13 14
  Sinusitis 6 10 6
  Pharyngitis 4 5 6
  Coughing 2 2 4
  Bronchitis 2 3 3
  Dyspnea 2 1 3
Skin and Appendages Disorders
  Pruritis 2 4 2
Special Sense Other, Disorders
  Taste perversion 1 15 8
Urinary System Disorders
  Urinary tract infection 2 4 2
Vision Disorders
  Blurred vision Blurred vision was the most common term considered as vision abnormal. Blurred vision was an included term that accounted for >50% of reactions coded as vision abnormal, a preferred term. 2 4 2

Of the 1,135 patients exposed to TOPAMAX ® in the adult placebo-controlled studies, 25% of TOPAMAX ®-treated patients discontinued due to adverse reactions, compared to 10% of the 445 placebo-treated patients. The adverse reactions associated with discontinuing therapy in the TOPAMAX ®-treated patients included paresthesia (7%), fatigue (4%), nausea (4%), difficulty with concentration/attention (3%), insomnia (3%), anorexia (2%), and dizziness (2%).

Patients treated with TOPAMAX ® experienced mean percent reductions in body weight that were dose-dependent. This change was not seen in the placebo group. Mean changes of 0%, -2%, -3%, and -4% were seen for the placebo group, TOPAMAX ® 50, 100, and 200 mg groups, respectively.

Pediatric Patients 12 to 17 Years of Age

In five, randomized, double-blind, placebo-controlled, parallel group clinical trials for the preventive treatment of migraine, most adverse reactions occurred more frequently during the titration period than during the maintenance period. Among adverse reactions with onset during titration, approximately half persisted into the maintenance period.

In four, fixed-dose, double-blind clinical trials for the preventive treatment of migraine in TOPAMAX ®-treated pediatric patients 12 to 17 years of age, the most common adverse reactions with TOPAMAX ® 100 mg that were seen at an incidence higher (≥5%) than in the placebo group were: paresthesia, upper respiratory tract infection, anorexia, and abdominal pain (see Table 9). Table 9 shows adverse reactions from the pediatric trial (Study 13 [see Clinical Studies (14.3)] ) in which 103 pediatric patients were treated with placebo or 50 mg or 100 mg of TOPAMAX ®, and three predominantly adult trials in which 49 pediatric patients (12 to 17 years of age) were treated with placebo or 50 mg, 100 mg or 200 mg of TOPAMAX ®. Table 9 also shows adverse reactions in pediatric patients in the controlled migraine trials when the incidence in a TOPAMAX ® dose group was at least 5 % or higher and greater than the incidence of placebo. Many adverse reactions shown in Table 9 indicate a dose-dependent relationship. The incidence of some adverse reactions (e.g., allergy, fatigue, headache, anorexia, insomnia, somnolence, and viral infection) was dose-related and greater at higher than recommended TOPAMAX ® dosing (200 mg daily) compared to the incidence of these adverse reactions at the recommended dosing (100 mg daily).

Table 9: Adverse Reactions in Pooled Double-Blind Studies for the Preventive Treatment of Migraine in Pediatric Patients 12 to 17 Years of Age 35 adolescent patients aged 12 to <16 years were also included in adverse reaction assessment for adults (Tables 11 and 12) , Incidence is based on the number of subjects experiencing at least 1 adverse event, not the number of events. , Included studies MIG-3006, MIGR-001, MIGR-002 and MIGR-003
TOPAMAX ® Dosage
Body System/
  Adverse Reaction
Placebo
(N=45)
%
50 mg/day
(N=46)
%
100 mg/day
(N=48)
%
Body as a Whole – General Disorders
  Fatigue 7 7 8
  Fever 2 4 6
Central & Peripheral Nervous System Disorders
  Paresthesia 7 20 19
  Dizziness 4 4 6
Gastrointestinal System Disorders
  Abdominal pain 9 7 15
  Nausea 4 4 8
Metabolic and Nutritional Disorders
  Weight loss 2 7 4
Psychiatric Disorders
  Anorexia 4 9 10
  Somnolence 2 2 6
  Insomnia 2 9 2
Resistance Mechanism Disorders
  Infection viral 4 4 8
Respiratory System Disorders
  Upper respiratory tract infection 11 26 23
  Rhinitis 2 7 6
  Sinusitis 2 9 4
  Coughing 0 7 2
Special Senses Other, Disorders
  Taste perversion 2 2 6
Vision Disorders
  Conjunctivitis 4 7 4

In the double-blind placebo-controlled studies, adverse reactions led to discontinuation of treatment in 8% of placebo patients compared with 6% of TOPAMAX ®-treated patients. Adverse reactions associated with discontinuing therapy that occurred in more than one TOPAMAX ®-treated patient were fatigue (1%), headache (1%), and somnolence (1%).

Increased Risk for Bleeding

TOPAMAX ® is associated with an increased risk for bleeding. In a pooled analysis of placebo-controlled studies of approved and unapproved indications, bleeding was more frequently reported as an adverse reaction for TOPAMAX ® than for placebo (4.5% versus 3.0% in adult patients, and 4.4% versus 2.3% in pediatric patients). In this analysis, the incidence of serious bleeding events for TOPAMAX ® and placebo was 0.3% versus 0.2% for adult patients, and 0.4% versus 0% for pediatric patients.

Adverse bleeding reactions reported with TOPAMAX ® ranged from mild epistaxis, ecchymosis, and increased menstrual bleeding to life-threatening hemorrhages. In patients with serious bleeding events, conditions that increased the risk for bleeding were often present, or patients were often taking drugs that cause thrombocytopenia (other antiepileptic drugs) or affect platelet function or coagulation (e.g., aspirin, nonsteroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, or warfarin or other anticoagulants).

Other Adverse Reactions Observed During Clinical Trials

Other adverse reactions seen during clinical trials were: abnormal coordination, eosinophilia, gingival bleeding, hematuria, hypotension, myalgia, myopia, postural hypotension, scotoma, suicide attempt, syncope, and visual field defect.

Laboratory Test Abnormalities

Adult Patients

In addition to changes in serum bicarbonate (i.e., metabolic acidosis), sodium chloride and ammonia, TOPAMAX ® was associated with changes in several clinical laboratory analytes in randomized, double-blind, placebo-controlled studies [see Warnings and Precautions (5.4, 5.12)]. Controlled trials of adjunctive TOPAMAX ® treatment of adults for partial-onset seizures showed an increased incidence of markedly decreased serum phosphorus (6% TOPAMAX ® versus 2% placebo), markedly increased serum alkaline phosphatase (3% TOPAMAX ® versus 1% placebo), and decreased serum potassium (0.4 % TOPAMAX ® versus 0.1 % placebo).

Pediatric Patients

In pediatric patients (1–24 months) receiving adjunctive TOPAMAX ® for partial-onset seizures, there was an increased incidence for an increased result (relative to normal analyte reference range) associated with TOPAMAX ® (vs placebo) for the following clinical laboratory analytes: creatinine, BUN, alkaline phosphatase, and total protein, The incidence was also increased for a decreased result for bicarbonate (i.e., metabolic acidosis), and potassium with TOPAMAX ® (vs placebo) [see Use in Specific Populations (8.4)]. TOPAMAX ® is not indicated for partial-onset seizures in pediatric patients less than 2 years of age.

In pediatric patients (ranging from 6–17 years of age) receiving TOPAMAX ® for the preventive treatment of migraine, there was an increased incidence for an increased result (relative to normal analyte reference range) associated with TOPAMAX ® (vs placebo) for the following clinical laboratory analytes: creatinine, BUN, uric acid, chloride, ammonia, alkaline phosphatase, total protein, platelets, and eosinophils, The incidence was also increased for a decreased result for phosphorus, bicarbonate, total white blood count, and neutrophils [see Use in Specific Populations (8.4)] . TOPAMAX ® is not indicated for the preventive treatment of migraine in pediatric patients less than 12 years of age.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of TOPAMAX ®. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole-General Disorders: oligohydrosis and hyperthermia [see Warnings and Precautions (5.3)] , hyperammonemia, hyperammonemic encephalopathy [see Warnings and Precautions (5.12)], hypothermia with concomitant valproic acid [see Warnings and Precautions (5.14)]

Gastrointestinal System Disorders: hepatic failure (including fatalities), hepatitis, pancreatitis

Skin and Appendage Disorders: bullous skin reactions (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis) [see Warnings and Precautions (5.11)] , pemphigus

Urinary System Disorders: kidney stones, nephrocalcinosis [see Warnings and Precautions (5.4, 5.13)]

Vision Disorders: acute myopia, secondary angle closure glaucoma [see Warnings and Precautions (5.1)] , maculopathy

Hematological Disorders: decrease of the International Normalized Ratio (INR) or prothrombin time when given concomitantly with vitamin K antagonist anticoagulant medications such as warfarin.

7 DRUG INTERACTIONS

  • Contraceptives: decreased contraceptive efficacy and increased breakthrough bleeding, especially at doses greater than 200 mg/day ( 7.4)
  • Monitor lithium levels if lithium is used with high-dose TOPAMAX ® ( 7.7)

7.1 Antiepileptic Drugs

Concomitant administration of phenytoin or carbamazepine with TOPAMAX ® resulted in a clinically significant decrease in plasma concentrations of topiramate when compared to TOPAMAX ® given alone. A dosage adjustment may be needed [see Dosage and Administration (2.1), Clinical Pharmacology (12.3)].

Concomitant administration of valproic acid and TOPAMAX ® has been associated with hypothermia and hyperammonemia with and without encephalopathy. Examine blood ammonia levels in patients in whom the onset of hypothermia has been reported [see Warnings and Precautions (5.12, 5.14), Clinical Pharmacology (12.3)] .

7.2 Other Carbonic Anhydrase Inhibitors

Concomitant use of topiramate, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., zonisamide or acetazolamide) may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Therefore, patients given TOPAMAX ® concomitantly with another carbonic anhydrase inhibitor should be monitored particularly closely for the appearance or worsening of metabolic acidosis [see Clinical Pharmacology (12.3)] .

7.3 CNS Depressants

Concomitant administration of TOPAMAX ® and alcohol or other CNS depressant drugs has not been evaluated in clinical studies. Because of the potential of topiramate to cause CNS depression, as well as other cognitive and/or neuropsychiatric adverse reactions, TOPAMAX ® should be used with extreme caution if used in combination with alcohol and other CNS depressants.

7.4 Contraceptives

The possibility of decreased contraceptive efficacy and increased breakthrough bleeding may occur in patients taking contraceptive products with TOPAMAX ®. Patients taking estrogen-containing or progestin-only contraceptives should be asked to report any change in their bleeding patterns. Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding [see Clinical Pharmacology (12.3)].

7.5 Hydrochlorothiazide (HCTZ)

Topiramate C max and AUC increased when HCTZ was added to TOPAMAX ®. The clinical significance of this change is unknown. The addition of HCTZ to TOPAMAX ® may require a decrease in the TOPAMAX ® dose [see Clinical Pharmacology (12.3)] .

7.6 Pioglitazone

A decrease in the exposure of pioglitazone and its active metabolites were noted with the concurrent use of pioglitazone and TOPAMAX ® in a clinical trial. The clinical relevance of these observations is unknown; however, when TOPAMAX ® is added to pioglitazone therapy or pioglitazone is added to TOPAMAX ® therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state [see Clinical Pharmacology (12.3)] .

7.7 Lithium

An increase in systemic exposure of lithium following TOPAMAX ® doses of up to 600 mg/day can occur. Lithium levels should be monitored when co-administered with high-dose TOPAMAX ® [see Clinical Pharmacology (12.3)] .

7.8 Amitriptyline

Some patients may experience a large increase in amitriptyline concentration in the presence of TOPAMAX ® and any adjustments in amitriptyline dose should be made according to the patient's clinical response and not on the basis of plasma levels [see Clinical Pharmacology (12.3)] .

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to TOPAMAX ® during pregnancy. Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll-free number 1-888-233-2334. Information about the North American Drug Pregnancy Registry can be found at http://www.aedpregnancyregistry.org/ .

Risk Summary

TOPAMAX ® can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have an increased risk of major congenital malformations, including but not limited to cleft lip and/or cleft palate (oral clefts), and of being small for gestational age (SGA) [see Human Data] . SGA has been observed at all doses and appears to be dose-dependent. The prevalence of SGA is greater in infants of women who received higher doses of topiramate during pregnancy. In addition, the prevalence of SGA in infants of women who continued topiramate use until later in pregnancy is higher compared to the prevalence in infants of women who stopped topiramate use before the third trimester.

In multiple animal species, topiramate produced developmental toxicity, including increased incidences of fetal malformations, in the absence of maternal toxicity at clinically relevant doses [see Animal Data] .

All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2–4% and 15–20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Consider the benefits and risks of topiramate when prescribing this drug to women of childbearing potential, particularly when topiramate is considered for a condition not usually associated with permanent injury or death. Because of the risk of oral clefts to the fetus, which occur in the first trimester of pregnancy, all women of childbearing potential should be informed of the potential risk to the fetus from exposure to topiramate. Women who are planning a pregnancy should be counseled regarding the relative risks and benefits of topiramate use during pregnancy, and alternative therapeutic options should be considered for these patients.

Labor or Delivery

Although the effect of TOPAMAX ® on labor and delivery in humans has not been established, the development of topiramate-induced metabolic acidosis in the mother and/or in the fetus might affect the fetus' ability to tolerate labor.

TOPAMAX ® treatment can cause metabolic acidosis [see Warnings and Precautions (5.4)]. The effect of topiramate-induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy (due to other causes) can cause decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus' ability to tolerate labor. Pregnant patients should be monitored for metabolic acidosis and treated as in the nonpregnant state [see Warnings and Precautions (5.4)]. Newborns of mothers treated with TOPAMAX ® should be monitored for metabolic acidosis because of transfer of topiramate to the fetus and possible occurrence of transient metabolic acidosis following birth.

Based on limited information, topiramate has also been associated with pre-term labor and premature delivery.

Data

Human Data

Data from pregnancy registries indicate an increased risk of major congenital malformations, including but not limited to oral clefts in infants exposed to topiramate during the first trimester of pregnancy. Other than oral clefts, no specific pattern of major congenital malformations or grouping of major congenital malformation types were observed. In the NAAED pregnancy registry, when topiramate-exposed infants with only oral clefts were excluded, the prevalence of major congenital malformations (4.1%) was higher than that in infants exposed to a reference AED (1.8%) or in infants with mothers without epilepsy and without exposure to AEDs (1.1%). The prevalence of oral clefts among topiramate-exposed infants (1.4%) was higher than the prevalence in infants exposed to a reference AED (0.3%) or the prevalence in infants with mothers without epilepsy and without exposure to AEDs (0.11%). It was also higher than the background prevalence in United States (0.17%) as estimated by the Centers for Disease Control and Prevention (CDC). The relative risk of oral clefts in topiramate-exposed pregnancies in the NAAED Pregnancy Registry was 12.5 (95% Confidence Interval [CI]5.9–26.37) as compared to the risk in a background population of untreated women. The UK Epilepsy and Pregnancy Register reported a prevalence of oral clefts among infants exposed to topiramate monotherapy (3.2%) that was 16 times higher than the background rate in the UK (0.2%).

Data from the NAAED pregnancy registry and a population-based birth registry cohort indicate that exposure to topiramate in utero is associated with an increased risk of SGA newborns (birth weight <10th percentile). In the NAAED pregnancy registry, 19.7% of topiramate-exposed newborns were SGA compared to 7.9% of newborns exposed to a reference AED and 5.4% of newborns of mothers without epilepsy and without AED exposure. In the Medical Birth Registry of Norway (MBRN), a population-based pregnancy registry, 25% of newborns in the topiramate monotherapy exposure group were SGA compared to 9 % in the comparison group unexposed to AEDs. The long-term consequences of the SGA findings are not known.

8.2 Lactation

Risk Summary

Topiramate is excreted in human milk [see Data] . The effects of topiramate on milk production are unknown. Diarrhea and somnolence have been reported in breastfed infants whose mothers receive topiramate treatment.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for TOPAMAX ® and any potential adverse effects on the breastfed infant from TOPAMAX ® or from the underlying maternal condition.

Data

Human Data

Limited data from 5 women with epilepsy treated with topiramate during lactation showed drug levels in milk similar to those in maternal plasma.

8.3 Females and Males of Reproductive Potential

Contraception

Women of childbearing potential who are not planning a pregnancy should use effective contraception because of the risk of major congenital malformations, including oral clefts, and the risk of infants being SGA [see Drug Interactions (7.4) and Use in Specific Populations 8.1] .

8.4 Pediatric Use

Adjunctive Treatment for Epilepsy

Pediatric Patients 2 Years of Age and Older

The safety and effectiveness of TOPAMAX ® as adjunctive therapy for the treatment of partial-onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome have been established in pediatric patients 2 years of age and older [see Adverse Reactions (6.1) and Clinical Studies (14.2)] .

Pediatric Patients Below the Age of 2 Years

Safety and effectiveness in patients below the age of 2 years have not been established for the adjunctive therapy treatment of partial-onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome. In a single randomized, double-blind, placebo-controlled investigational trial, the efficacy, safety, and tolerability of topiramate oral liquid and sprinkle formulations as an adjunct to concurrent antiepileptic drug therapy in pediatric patients 1 to 24 months of age with refractory partial-onset seizures were assessed. After 20 days of double-blind treatment, topiramate (at fixed doses of 5, 15, and 25 mg/kg/day) did not demonstrate efficacy compared with placebo in controlling seizures.

In general, the adverse reaction profile for TOPAMAX ® in this population was similar to that of older pediatric patients, although results from the above controlled study and an open-label, long-term extension study in these pediatric patients 1 to 24 months old suggested some adverse reactions/toxicities (not previously observed in older pediatric patients and adults; i.e., growth/length retardation, certain clinical laboratory abnormalities, and other adverse reactions/toxicities that occurred with a greater frequency and/or greater severity than had been recognized previously from studies in older pediatric patients or adults for various indications).

These very young pediatric patients appeared to experience an increased risk for infections (any topiramate dose 12%, placebo 0%) and of respiratory disorders (any topiramate dose 40%, placebo 16%). The following adverse reactions were observed in at least 3% of patients on topiramate and were 3% to 7% more frequent than in patients on placebo: viral infection, bronchitis, pharyngitis, rhinitis, otitis media, upper respiratory infection, cough, and bronchospasm. A generally similar profile was observed in older pediatric patients [see Adverse Reactions (6)] .

Topiramate resulted in an increased incidence of patients with increased creatinine (any topiramate dose 5%, placebo 0%), BUN (any topiramate dose 3%, placebo 0%), and protein (any topiramate dose 34%, placebo 6%), and an increased incidence of decreased potassium (any topiramate dose 7%, placebo 0%). This increased frequency of abnormal values was not dose-related. Creatinine was the only analyte showing a noteworthy increased incidence (topiramate 25 mg/kg/day 5%, placebo 0%) of a markedly abnormal increase. The significance of these findings is uncertain.

Topiramate treatment also produced a dose-related increase in the percentage of patients who had a shift from normal at baseline to high/increased (above the normal reference range) in total eosinophil count at the end of treatment. The incidence of these abnormal shifts was 6 % for placebo, 10% for 5 mg/kg/day, 9% for 15 mg/kg/day, 14% for 25 mg/kg/day, and 11% for any topiramate dose. There was a mean dose-related increase in alkaline phosphatase. The significance of these findings is uncertain.

Topiramate produced a dose-related increased incidence of hyperammonemia [see Warnings and Precautions (5.12)] .

Treatment with topiramate for up to 1 year was associated with reductions in Z SCORES for length, weight, and head circumference [see Warnings and Precautions (5.4), Adverse Reactions (6)] .

In open-label, uncontrolled experience, increasing impairment of adaptive behavior was documented in behavioral testing over time in this population. There was a suggestion that this effect was dose-related. However, because of the absence of an appropriate control group, it is not known if this decrement in function was treatment-related or reflects the patient's underlying disease (e.g., patients who received higher doses may have more severe underlying disease) [see Warnings and Precautions (5.6)] .

In this open-label, uncontrolled study, the mortality was 37 deaths/1000 patient years. It is not possible to know whether this mortality rate is related to topiramate treatment, because the background mortality rate for a similar, significantly refractory, young pediatric population (1–24 months) with partial epilepsy is not known.

Monotherapy Treatment for Epilepsy

Pediatric Patients 2 Years of Age and Older

The safety and effectiveness of TOPAMAX as monotherapy for the treatment of partial-onset seizures or primary generalized tonic-clonic seizures have been established in pediatric patients aged 2 years and older [see Adverse Reactions (6.1), Clinical Studies (14.1)] .

A one-year, active-controlled, open-label study with blinded assessments of bone mineral density (BMD) and growth in pediatric patients 4 to 15 years of age, including 63 patients with recent or new onset of epilepsy, was conducted to assess effects of TOPAMAX ® (N=28, 6–15 years of age) versus levetiracetam (N=35, 4–15 years of age) monotherapy on bone mineralization and on height and weight, which reflect growth. Effects on bone mineralization were evaluated via dual-energy X-ray absorptiometry and blood markers. Table 10 summarizes effects of TOPAMAX ® at 12 months for key safety outcomes including BMD, height, height velocity, and weight. All Least Square Mean values for TOPAMAX ® and the comparator were positive. Therefore, the Least Square Mean treatment differences shown reflect a TOPAMAX ®-induced attenuation of the key safety outcomes. Statistically significant effects were observed for decreases in BMD (and bone mineral content) in lumbar spine and total body less head and in weight. Subgroup analyses according to age demonstrated similar negative effects for all key safety outcomes (i.e., BMD, height, weight).

Table 10 Summary of TOPAMAX ® Treatment Difference Results at 12 Months for Key Safety Outcomes
Safety Parameter Treatment Difference in Least Square Means (95 % Confidence Interval)
Annual Change in BMD Lumbar Spine (g/cm 2) -0.036 (-0.058, -0.014)
Annual Change in BMD TBLH TBLH=total body less head (g/cm 2) -0.026 (-0.039, -0.012)
Annual Change in Height (cm) (4–9 years, Primary Analysis Population for Height) Whereas no patients were randomized to 2–5 year age subgroup for TOPAMAX ®, 5 patients (4–5 years) were randomized to the active control group. -0.84 (-2.67, 0.99)
Annual Change in Height (cm) (4–15 years) -0.75 (-2.21, 0.71)
Annual Change in Height (cm) (10–15 years) -1.01 (-3.64, 1.61)
Height Velocity (cm/year) (4–9 years) -1.00 (-2.76, 0.76)
Height Velocity (cm/year) (4–15 years) -0.98 (-2.33, 0.37)
Height Velocity (cm/year) (10–15 years) -0.96 (-3.24, 1.32)
Annual Change in Weight (kg) -2.05 (-3.66, -0.45)

Metabolic acidosis (serum bicarbonate < 20 mEq/L) was observed in all TOPAMAX ®-treated patients at some time in the study [see Warnings and Precautions (5.4)] . Over the whole study, 76% more TOPAMAX ®-treated patients experienced persistent metabolic acidosis (i.e. 2 consecutive visits with or final serum bicarbonate < 20 mEq/L) compared to levetiracetam -treated patients. Over the whole study, 35% more TOPAMAX ®-treated patients experienced a markedly abnormally low serum bicarbonate (i.e., absolute value < 17 mEq/L and ≥ 5 mEq/L decrease from pre-treatment), indicating the frequency of more severe metabolic acidosis, compared to levetiracetam -treated patients. The decrease in BMD at 12 months was correlated with decreased serum bicarbonate, suggesting that metabolic acidosis was at least a partial factor contributing to this adverse effect on BMD.

TOPAMAX ®-treated patients exhibited an increased risk for developing an increased serum creatinine and an increased serum glucose above the normal reference range compared to control patients.

Pediatric Patients Below the Age of 2 Years

Safety and effectiveness in patients below the age of 2 years have not been established for the monotherapy treatment of epilepsy.

Preventive Treatment of Migraine

Pediatric Patients 12 to 17 Years of Age

Safety and effectiveness of topiramate for the preventive treatment of migraine was studied in 5 double-blind, randomized, placebo-controlled, parallel-group trials in a total of 219 pediatric patients, at doses of 50 to 200 mg/day, or 2 to 3 mg/kg/day. These comprised a fixed dose study in 103 pediatric patients 12 to 17 years of age [see Clinical Studies (14.3)] , a flexible dose (2 to 3 mg/kg/day), placebo-controlled study in 157 pediatric patients 6 to 16 years of age (including 67 pediatric patients 12 to 16 years of age), and a total of 49 pediatric patients 12 to 17 years of age in 3 studies for the preventive treatment of migraine primarily in adults. Open-label extension phases of 3 studies enabled evaluation of long-term safety for up to 6 months after the end of the double-blind phase.

Efficacy of topiramate for the preventive treatment of migraine in pediatric patients 12 to 17 years of age is demonstrated for a 100 mg daily dose in Study 13 [see Clinical Studies (14.3)]. Efficacy of topiramate (2 to 3 mg/kg/day) for the preventive treatment of migraine was not demonstrated in a placebo-controlled trial of 157 pediatric patients (6 to 16 years of age) that included treatment of 67 pediatric patients (12 to 16 years of age) for 20 weeks.

In the pediatric trials (12 to 17 years of age) in which patients were randomized to placebo or a fixed daily dose of TOPAMAX ®, the most common adverse reactions with TOPAMAX ® that were seen at an incidence higher (≥5%) than in the placebo group were: paresthesia, upper respiratory tract infection, anorexia, and abdominal pain [see Adverse Reactions (6)] .

The most common cognitive adverse reaction in pooled double-blind studies in pediatric patients 12 to 17 years of age was difficulty with concentration/attention [see Warnings and Precautions (5.6)].

Markedly abnormally low serum bicarbonate values indicative of metabolic acidosis were reported in topiramate-treated pediatric migraine patients [see Warnings and Precautions (5.4)] .

In topiramate-treated pediatric patients (12 to 17 years of age) compared to placebo-treated patients, abnormally increased results were more frequent for creatinine, BUN, uric acid, chloride, ammonia, total protein, and platelets. Abnormally decreased results were observed with topiramate vs placebo treatment for phosphorus and bicarbonate [see Adverse Reactions (6.1)] .

Notable changes (increases and decreases) from baseline in systolic blood pressure, diastolic blood pressure, and pulse were observed occurred more commonly in pediatric patients treated with topiramate compared to pediatric patients treated with placebo [see Clinical Pharmacology (12.2)].

Pediatric Patients Below the Age of 12 Years

Safety and effectiveness in pediatric patients below the age of 12 years have not been established for the preventive treatment of migraine.

In a double-blind study in 90 pediatric patients 6 to 11 years of age (including 59 topiramate-treated and 31 placebo patients), the adverse reaction profile was generally similar to that seen in pooled double-blind studies of pediatric patients 12 to 17 years of age. The most common adverse reactions that occurred in TOPAMAX ®-treated pediatric patients 6 to 11 years of age, and at least twice as frequently than placebo, were gastroenteritis (12% topiramate, 6% placebo), sinusitis (10% topiramate, 3% placebo), weight loss (8% topiramate, 3% placebo) and paresthesia (7% topiramate, 0% placebo). Difficulty with concentration/attention occurred in 3 topiramate-treated patients (5%) and 0 placebo-treated patients.

The risk for cognitive adverse reaction was greater in younger patients (6 to 11 years of age) than in older patients (12 to 17 years of age) [see Warnings and Precautions (5.6)] .

Juvenile Animal Studies

When topiramate (0, 30, 90, and 300 mg/kg/day) was administered orally to rats during the juvenile period of development (postnatal days 12 to 50), bone growth plate thickness was reduced in males at the highest dose. The no-effect dose (90 mg/kg/day) for adverse developmental effects is approximately 2 times the maximum recommended pediatric dose (9 mg/kg/day) on a body surface area (mg/m 2) basis.

8.5 Geriatric Use

In clinical trials, 3% of patients were over age 60. No age-related differences in effectiveness or adverse effects were evident. However, clinical studies of topiramate did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently than younger subjects. Dosage adjustment may be necessary for elderly with age-related renal impairment (creatinine clearance rate <70 mL/min/1.73 m 2) resulting in reduced clearance [see Dosage and Administration (2.5), Clinical Pharmacology (12.3)] .

8.6 Renal Impairment

The clearance of topiramate is reduced in patients with moderate (creatinine clearance 30 to 69 mL/min/1.73 m 2) and severe (creatinine clearance <30 mL/min/1.73 m 2) renal impairment. A dosage adjustment is recommended in patients with moderate or severe renal impairment [see Dosage and Administration (2.5), Clinical Pharmacology (12.3)] .

8.7 Patients Undergoing Hemodialysis

Topiramate is cleared by hemodialysis at a rate that is 4 to 6 times greater than in a normal individual. A dosage adjustment may be required [see Dosage and Administration (2.6), Clinical Pharmacology (12.3)].

10 OVERDOSAGE

Overdoses of TOPAMAX ® have been reported. Signs and symptoms included convulsions, drowsiness, speech disturbance, blurred vision, diplopia, impaired mentation, lethargy, abnormal coordination, stupor, hypotension, abdominal pain, agitation, dizziness and depression. The clinical consequences were not severe in most cases, but deaths have been reported after overdoses involving TOPAMAX ®.

TOPAMAX ® overdose has resulted in severe metabolic acidosis [see Warnings and Precautions (5.4)] .

A patient who ingested a dose of TOPAMAX ® between 96 and 110 g was admitted to a hospital with a coma lasting 20 to 24 hours followed by full recovery after 3 to 4 days.

In the event of overdose, TOPAMAX ® should be discontinued and general supportive treatment given until clinical toxicity has been diminished or resolved. Hemodialysis is an effective means of removing topiramate from the body.

11 DESCRIPTION

Topiramate is a sulfamate-substituted monosaccharide. TOPAMAX ® (topiramate) Tablets are available as 25 mg, 50 mg, 100 mg, and 200 mg round tablets for oral administration. TOPAMAX ® (topiramate capsules) Sprinkle Capsules are available as 15 mg and 25 mg sprinkle capsules for oral administration as whole capsules or opened and sprinkled onto soft food.

Topiramate is a white crystalline powder with a bitter taste. Topiramate is most soluble in alkaline solutions containing sodium hydroxide or sodium phosphate and having a pH of 9 to 10. It is freely soluble in acetone, chloroform, dimethylsulfoxide, and ethanol. The solubility in water is 9.8 mg/mL. Its saturated solution has a pH of 6.3. Topiramate has the molecular formula C 12H 21NO 8S and a molecular weight of 339.36. Topiramate is designated chemically as 2,3:4,5-Di- O-isopropylidene-β-D-fructopyranose sulfamate and has the following structural formula:

Chemical Structure

TOPAMAX ® Tablets contain the following inactive ingredients: carnauba wax, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, pregelatinized starch, purified water, sodium starch glycolate, synthetic iron oxide, and titanium dioxide.

TOPAMAX ® Sprinkle Capsules contain topiramate-coated beads in a hard gelatin capsule. The inactive ingredients are black pharmaceutical ink, cellulose acetate, gelatin, povidone, sodium lauryl sulfate, sorbitan monolaurate, sugar spheres (sucrose and starch) and titanium dioxide.

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The precise mechanisms by which topiramate exerts its anticonvulsant and preventive migraine effects are unknown; however, preclinical studies have revealed four properties that may contribute to topiramate's efficacy for epilepsy and the preventive treatment of migraine. Electrophysiological and biochemical evidence suggests that topiramate, at pharmacologically relevant concentrations, blocks voltage-dependent sodium channels, augments the activity of the neurotransmitter gamma-aminobutyrate at some subtypes of the GABA-A receptor, antagonizes the AMPA/kainate subtype of the glutamate receptor, and inhibits the carbonic anhydrase enzyme, particularly isozymes II and IV.

12.2 Pharmacodynamics

Topiramate has anticonvulsant activity in rat and mouse maximal electroshock seizure (MES) tests. Topiramate is only weakly effective in blocking clonic seizures induced by the GABA A receptor antagonist, pentylenetetrazole. Topiramate is also effective in rodent models of epilepsy, which include tonic and absence-like seizures in the spontaneous epileptic rat (SER) and tonic and clonic seizures induced in rats by kindling of the amygdala or by global ischemia.

Changes (increases and decreases) from baseline in vital signs (systolic blood pressure-SBP, diastolic blood pressure-DBP, pulse) occurred more frequently in pediatric patients (6 to 17 years) treated with various daily doses of topiramate (50 mg, 100 mg, 200 mg, 2 to 3 mg/kg) than in patients treated with placebo in controlled trials for the preventive treatment of migraine. The most notable changes were SBP <90 mm Hg, DBP <50 mm Hg, SBP or DBP increases or decreases ≥20 mm Hg, and pulse increases or decreases ≥30 beats per minute. These changes were often dose-related, and were most frequently associated with the greatest treatment difference at the 200 mg dose level. Systematic collection of orthostatic vital signs has not been conducted. The clinical significance of these various changes in vital signs has not been clearly established.

12.3 Pharmacokinetics

The sprinkle formulation is bioequivalent to the immediate-release tablet formulation and, therefore, may be substituted as a therapeutic equivalent.

Absorption of topiramate is rapid, with peak plasma concentrations occurring at approximately 2 hours following a 400 mg oral dose. The relative bioavailability of topiramate from the tablet formulation is about 80% compared to a solution. The bioavailability of topiramate is not affected by food.

The pharmacokinetics of topiramate are linear with dose proportional increases in plasma concentration over the dose range studied (200 to 800 mg/day). The mean plasma elimination half-life is 21 hours after single or multiple doses. Steady-state is thus reached in about 4 days in patients with normal renal function. Topiramate is 15% to 41% bound to human plasma proteins over the blood concentration range of 0.5 to 250 µg/mL. The fraction bound decreased as blood concentration increased.

Carbamazepine and phenytoin do not alter the binding of topiramate. Sodium valproate, at 500 µg/mL (a concentration 5 to 10 times higher than considered therapeutic for valproate) decreased the protein binding of topiramate from 23% to 13%. Topiramate does not influence the binding of sodium valproate.

Metabolism and Excretion

Topiramate is not extensively metabolized and is primarily eliminated unchanged in the urine (approximately 70% of an administered dose). Six metabolites have been identified in humans, none of which constitutes more than 5% of an administered dose. The metabolites are formed via hydroxylation, hydrolysis, and glucuronidation. There is evidence of renal tubular reabsorption of topiramate. In rats, given probenecid to inhibit tubular reabsorption, along with topiramate, a significant increase in renal clearance of topiramate was observed. This interaction has not been evaluated in humans. Overall, oral plasma clearance (CL/F) is approximately 20 to 30 mL/min in adults following oral administration.

Specific Populations

Renal Impairment

The clearance of topiramate was reduced by 42% in subjects with moderate renal impairment (creatinine clearance 30 to 69 mL/min/1.73 m 2) and by 54% in subjects with severe renal impairment (creatinine clearance <30 mL/min/1.73 m 2) compared to subjects with normal renal function (creatinine clearance >70 mL/min/1.73 m 2) [see Dosage and Administration (2.4) and (2.5)] .

Hemodialysis

Topiramate is cleared by hemodialysis. Using a high-efficiency, counterflow, single pass-dialysate hemodialysis procedure, topiramate dialysis clearance was 120 mL/min with blood flow through the dialyzer at 400 mL/min. This high clearance (compared to 20 to 30 mL/min total oral clearance in healthy adults) will remove a clinically significant amount of topiramate from the patient over the hemodialysis treatment period [see Dosage and Administration (2.6), Use in Specific Populations (8.7)] .

Hepatic Impairment

Plasma clearance of topiramate decreased a mean of 26% in patients with moderate to severe hepatic impairment.

Age, Gender, and Race

The pharmacokinetics of topiramate in elderly subjects (65 to 85 years of age, N=16) were evaluated in a controlled clinical study. The elderly subject population had reduced renal function (creatinine clearance [-20%]) compared to young adults. Following a single oral 100 mg dose, maximum plasma concentration for elderly and young adults was achieved at approximately 1 to 2 hours. Reflecting the primary renal elimination of topiramate, topiramate plasma and renal clearance were reduced 21% and 19%, respectively, in elderly subjects, compared to young adults. Similarly, topiramate half-life was longer (13%) in the elderly. Reduced topiramate clearance resulted in slightly higher maximum plasma concentration (23%) and AUC (25%) in elderly subjects than observed in young adults. Topiramate clearance is decreased in the elderly only to the extent that renal function is reduced [see Dosage and Administration (2.4) and Use in Specific Populations (8.5)] .

Clearance of topiramate in adults was not affected by gender or race.

Pediatric Pharmacokinetics

Pharmacokinetics of topiramate were evaluated in patients age 2 to <16 years. Patients received either no or a combination of other antiepileptic drugs. A population pharmacokinetic model was developed on the basis of pharmacokinetic data from relevant topiramate clinical studies. This dataset contained data from 1217 subjects including 258 pediatric patients age 2 to <16 years (95 pediatric patients <10 years of age).

Pediatric patients on adjunctive treatment exhibited a higher oral clearance (L/h) of topiramate compared to patients on monotherapy, presumably because of increased clearance from concomitant enzyme-inducing antiepileptic drugs. In comparison, topiramate clearance per kg is greater in pediatric patients than in adults and in young pediatric patients (down to 2 years) than in older pediatric patients. Consequently, the plasma drug concentration for the same mg/kg/day dose would be lower in pediatric patients compared to adults and also in younger pediatric patients compared to older pediatric patients. Clearance was independent of dose.

As in adults, hepatic enzyme-inducing antiepileptic drugs decrease the steady state plasma concentrations of topiramate.

Drug Interactions

In vitro studies indicate that topiramate does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, or CYP3A4/5 isozymes. In vitro studies indicate that topiramate is a mild inhibitor of CYP2C19 and a mild inducer of CYP3A4.

Antiepileptic Drugs

Potential interactions between topiramate and standard AEDs were assessed in controlled clinical pharmacokinetic studies in patients with epilepsy. The effects of these interactions on mean plasma AUCs are summarized in Table 11.

In Table 11, the second column (AED concentration) describes what happens to the concentration of the co-administered AED listed in the first column when topiramate is added. The third column (topiramate concentration) describes how the co-administration of a drug listed in the first column modifies the concentration of topiramate when compared to TOPAMAX ® given alone.

Table 11: Summary of AED Interactions with TOPAMAX ®
AED
Co-administered
AED
Concentration
Topiramate
Concentration
NC = Less than 10% change in plasma concentration.
AED = Antiepileptic drug.
NE = Not Evaluated.
TPM = Topiramate
Phenytoin NC or 25% increase = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxide = Is not administered but is an active metabolite of carbamazepine. NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease

Oral Contraceptives

In a pharmacokinetic interaction study in healthy volunteers with a concomitantly administered combination oral contraceptive product containing 1 mg norethindrone (NET) plus 35 mcg ethinyl estradiol (EE), TOPAMAX ®, given in the absence of other medications at doses of 50 to 200 mg/day, was not associated with statistically significant changes in mean exposure (AUC) to either component of the oral contraceptive. In another study, exposure to EE was statistically significantly decreased at doses of 200, 400, and 800 mg/day (18%, 21%, and 30%, respectively) when given as adjunctive therapy in patients taking valproic acid. In both studies, TOPAMAX ® (50 mg/day to 800 mg/day) did not significantly affect exposure to NET and there was no significant dose-dependent change in EE exposure for doses of 50 to 200 mg/day. The clinical significance of the changes observed is not known [see Drug Interactions (7.4)] .

Digoxin

In a single-dose study, serum digoxin AUC was decreased by 12% with concomitant TOPAMAX ® administration. The clinical relevance of this observation has not been established.

Hydrochlorothiazide

A drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of hydrochlorothiazide (HCTZ) (25 mg every 24 hours) and topiramate (96 mg every 12 hours) when administered alone and concomitantly. The results of this study indicate that topiramate C max increased by 27% and AUC increased by 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not significantly influenced by the concomitant administration of topiramate. Clinical laboratory results indicated decreases in serum potassium after topiramate or HCTZ administration, which were greater when HCTZ and topiramate were administered in combination.

Metformin

A drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of metformin (500 mg every 12 hours) and topiramate in plasma when metformin was given alone and when metformin and topiramate (100 mg every 12 hours) were given simultaneously. The results of this study indicated that the mean metformin C max and AUC 0–12h increased by 18% and 25%, respectively, when topiramate was added. Topiramate did not affect metformin t max. The clinical significance of the effect of topiramate on metformin pharmacokinetics is not known. Oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect of metformin on topiramate pharmacokinetics is unclear.

Pioglitazone

A drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of topiramate and pioglitazone when administered alone and concomitantly. A 15% decrease in the AUC τ,ss of pioglitazone with no alteration in C max,ss was observed. This finding was not statistically significant. In addition, a 13% and 16% decrease in C max,ss and AUC τ,ss respectively, of the active hydroxy-metabolite was noted as well as a 60% decrease in C max,ss and AUC τ,ss of the active keto-metabolite. The clinical significance of these findings is not known.

Glyburide

A drug-drug interaction study conducted in patients with type 2 diabetes evaluated the steady-state pharmacokinetics of glyburide (5 mg/day) alone and concomitantly with topiramate (150 mg/day). There was a 22% decrease in C max and a 25% reduction in AUC 24 for glyburide during topiramate administration. Systemic exposure (AUC) of the active metabolites, 4- trans-hydroxy-glyburide (M1) and 3- cis-hydroxyglyburide (M2), was also reduced by 13% and 15%, and C max was reduced by 18% and 25%, respectively. The steady-state pharmacokinetics of topiramate were unaffected by concomitant administration of glyburide.

Lithium

In patients, the pharmacokinetics of lithium were unaffected during treatment with topiramate at doses of 200 mg/day; however, there was an observed increase in systemic exposure of lithium (27% for C max and 26% for AUC) following topiramate doses up to 600 mg/day [see Drug Interactions (7.7)] .

Haloperidol

The pharmacokinetics of a single dose of haloperidol (5 mg) were not affected following multiple dosing of topiramate (100 mg every 12 hr) in 13 healthy adults (6 males, 7 females).

Amitriptyline

There was a 12% increase in AUC and C max for amitriptyline (25 mg per day) in 18 healthy subjects (9 males, 9 females) receiving 200 mg/day of TOPAMAX ®.

Sumatriptan

Multiple dosing of topiramate (100 mg every 12 hours) in 24 healthy volunteers (14 males, 10 females) did not affect the pharmacokinetics of single-dose sumatriptan either orally (100 mg) or subcutaneously (6 mg).

Risperidone

When administered concomitantly with topiramate at escalating doses of 100, 250, and 400 mg/day, there was a reduction in risperidone systemic exposure (16% and 33% for steady-state AUC at the 250 and 400 mg/day doses of topiramate). No alterations of 9-hydroxyrisperidone levels were observed. Co-administration of topiramate 400 mg/day with risperidone resulted in a 14% increase in C max and a 12% increase in AUC 12 of topiramate. There were no clinically significant changes in the systemic exposure of risperidone plus 9-hydroxyrisperidone or of topiramate; therefore, this interaction is not likely to be of clinical significance.

Propranolol

Multiple dosing of topiramate (200 mg/day) in 34 healthy volunteers (17 males, 17 females) did not affect the pharmacokinetics of propranolol following daily 160 mg doses. Propranolol doses of 160 mg/day in 39 volunteers (27 males, 12 females) had no effect on the exposure to topiramate, at a dose of 200 mg/day of topiramate.

Dihydroergotamine

Multiple dosing of topiramate (200 mg/day) in 24 healthy volunteers (12 males, 12 females) did not affect the pharmacokinetics of a 1 mg subcutaneous dose of dihydroergotamine. Similarly, a 1 mg subcutaneous dose of dihydroergotamine did not affect the pharmacokinetics of a 200 mg/day dose of topiramate in the same study.

Diltiazem

Co-administration of diltiazem (240 mg Cardizem CD ®) with topiramate (150 mg/day) resulted in a 10% decrease in C max and a 25% decrease in diltiazem AUC, a 27% decrease in C max and an 18% decrease in des-acetyl diltiazem AUC, and no effect on N-desmethyl diltiazem. Co-administration of topiramate with diltiazem resulted in a 16% increase in C max and a 19% increase in AUC 12 of topiramate.

Venlafaxine

Multiple dosing of TOPAMAX ® (150 mg/day) in healthy volunteers did not affect the pharmacokinetics of venlafaxine or O-desmethyl venlafaxine. Multiple dosing of venlafaxine (150 mg) did not affect the pharmacokinetics of topiramate.

13 NON-CLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

An increase in urinary bladder tumors was observed in mice given topiramate (0, 20, 75, and 300 mg/kg/day) in the diet for 21 months. The increase in the incidence of bladder tumors in males and females receiving 300 mg/kg/day was primarily due to the increased occurrence of a smooth muscle tumor considered histomorphologically unique to mice. The higher of the doses not associated with an increase in tumors (75 mg/kg/day) is equivalent to the maximum recommended human dose (MRHD) for epilepsy (400 mg), and approximately 4 times the MRHD for migraine (100 mg) on a mg/m 2 basis. The relevance of this finding to human carcinogenic risk is uncertain. No evidence of carcinogenicity was seen in rats following oral administration of topiramate for 2 years at doses up to 120 mg/kg/day (approximately 3 times the MRHD for epilepsy and 12 times the MRHD for migraine on a mg/m 2 basis).

Mutagenesis

Topiramate did not demonstrate genotoxic potential when tested in a battery of in vitro and in vivo assays. Topiramate was not mutagenic in the Ames test or the in vitro mouse lymphoma assay; it did not increase unscheduled DNA synthesis in rat hepatocytes in vitro; and it did not increase chromosomal aberrations in human lymphocytes in vitro or in rat bone marrow in vivo.

Impairment of Fertility

No adverse effects on male or female fertility were observed in rats administered topiramate orally at doses up to 100 mg/kg/day (2.5 times the MRHD for epilepsy and 10 times the MRHD for migraine on a mg/m 2 basis) prior to and during mating and early pregnancy.

14 CLINICAL STUDIES

The studies described in the following sections were conducted using TOPAMAX ® (topiramate) Tablets.

14.1 Monotherapy Epilepsy

Patients with Partial-Onset or Primary Generalized Tonic-Clonic Seizures

Adults and Pediatric Patients 10 Years of Age and Older

The effectiveness of TOPAMAX ® as initial monotherapy in adults and pediatric patients 10 years of age and older with partial-onset or primary generalized tonic-clonic seizures was established in a multicenter, randomized, double-blind, parallel-group trial (Study 1).

Study 1 was conducted in 487 patients diagnosed with epilepsy (6 to 83 years of age) who had 1 or 2 well-documented seizures during the 3-month retrospective baseline phase who then entered the study and received TOPAMAX ® 25 mg/day for 7 days in an open-label fashion. Forty-nine percent of patients had no prior AED treatment and 17% had a diagnosis of epilepsy for greater than 24 months. Any AED therapy used for temporary or emergency purposes was discontinued prior to randomization. In the double-blind phase, 470 patients were randomized to titrate up to 50 mg/day or 400 mg/day. If the target dose could not be achieved, patients were maintained on the maximum tolerated dose. Fifty-eight percent of patients achieved the maximal dose of 400 mg/day for >2 weeks, and patients who did not tolerate 150 mg/day were discontinued.

The primary efficacy assessment was a between-group comparison of time to first seizure during the double-blind phase. Comparison of the Kaplan-Meier survival curves of time to first seizure favored the TOPAMAX ® 400 mg/day group over the TOPAMAX ® 50 mg/day group (Figure 1). The treatment effects with respect to time to first seizure were consistent across various patient subgroups defined by age, sex, geographic region, baseline body weight, baseline seizure type, time since diagnosis, and baseline AED use.

Figure 1: Kaplan-Meier Estimates of Cumulative Rates for Time to First Seizure in Study 1
Figure 1
Figure 1

Pediatric Patients 2 to 9 Years of Age

The conclusion that TOPAMAX ® is effective as initial monotherapy in pediatric patients 2 to 9 years of age with partial-onset or primary generalized tonic-clonic seizures was based on a pharmacometric bridging approach using data from the controlled epilepsy trials described in labeling. This approach consisted of first showing a similar exposure response relationship between pediatric patients down to 2 years of age and adults when TOPAMAX ® was given as adjunctive therapy. Similarity of exposure-response was also demonstrated in pediatric patients 6 to less than 16 years of age and adults when TOPAMAX ® was given as initial monotherapy. Specific dosing in pediatric patients 2 to 9 years of age was derived from simulations utilizing plasma exposure ranges observed in pediatric and adult patients treated with TOPAMAX ® initial monotherapy [see Dosage and Administration (2.1)] .

14.2 Adjunctive Therapy Epilepsy

Adult Patients With Partial-Onset Seizures

The effectiveness of TOPAMAX ® as an adjunctive treatment for adults with partial-onset seizures was established in six multicenter, randomized, double-blind, placebo-controlled trials (Studies 2, 3, 4, 5, 6, and 7), two comparing several dosages of TOPAMAX ® and placebo and four comparing a single dosage with placebo, in patients with a history of partial-onset seizures, with or without secondarily generalized seizures.

Patients in these studies were permitted a maximum of two antiepileptic drugs (AEDs) in addition to TOPAMAX ® tablets or placebo. In each study, patients were stabilized on optimum dosages of their concomitant AEDs during baseline phase lasting between 4 and 12 weeks. Patients who experienced a pre-specified minimum number of partial-onset seizures, with or without secondary generalization, during the baseline phase (12 seizures for 12-week baseline, 8 for 8-week baseline or 3 for 4-week baseline) were randomly assigned to placebo or a specified dose of TOPAMAX ® tablets in addition to their other AEDs.

Following randomization, patients began the double-blind phase of treatment. In five of the six studies, patients received active drug beginning at 100 mg per day; the dose was then increased by 100 mg or 200 mg/day increments weekly or every other week until the assigned dose was reached, unless intolerance prevented increases. In the sixth study (Study 7), the 25 or 50 mg/day initial doses of topiramate were followed by respective weekly increments of 25 or 50 mg/day until the target dose of 200 mg/day was reached. After titration, patients entered a 4, 8 or 12-week stabilization period. The numbers of patients randomized to each dose and the actual mean and median doses in the stabilization period are shown in Table 12.

Pediatric Patients 2 to 16 Years of Age with Partial-Onset Seizures

The effectiveness of TOPAMAX ® as an adjunctive treatment for pediatric patients 2 to 16 years of age with partial-onset seizures was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 8), comparing TOPAMAX ® and placebo in patients with a history of partial-onset seizures, with or without secondarily generalized seizures (see Table 13).

Patients in this study were permitted a maximum of two antiepileptic drugs (AEDs) in addition to TOPAMAX ® tablets or placebo. In this study, patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least six partial-onset seizures, with or without secondarily generalized seizures, during the baseline phase were randomly assigned to placebo or TOPAMAX ® tablets in addition to their other AEDs.

Following randomization, patients began the double-blind phase of treatment. Patients received active drug beginning at 25 or 50 mg/day; the dose was then increased by 25 mg to 150 mg/day increments every other week until the assigned dosage of 125, 175, 225, or 400 mg/day based on patients' weight to approximate a dosage of 6 mg/kg/day was reached, unless intolerance prevented increases. After titration, patients entered an 8-week stabilization period.

Patients With Primary Generalized Tonic-Clonic Seizures

The effectiveness of TOPAMAX ® as an adjunctive treatment for primary generalized tonic-clonic seizures in patients 2 years of age and older was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 9), comparing a single dosage of TOPAMAX ® and placebo (see Table 13).

Patients in Study 9 were permitted a maximum of two antiepileptic drugs (AEDs) in addition to TOPAMAX ® or placebo. Patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least three primary generalized tonic-clonic seizures during the baseline phase were randomly assigned to placebo or TOPAMAX ® in addition to their other AEDs.

Following randomization, patients began the double-blind phase of treatment. Patients received active drug beginning at 50 mg/day for four weeks; the dose was then increased by 50 mg to 150 mg/day increments every other week until the assigned dose of 175, 225, or 400 mg/day based on patients' body weight to approximate a dosage of 6 mg/kg/day was reached, unless intolerance prevented increases. After titration, patients entered a 12-week stabilization period.

Patients With Lennox-Gastaut Syndrome

The effectiveness of TOPAMAX ® as an adjunctive treatment for seizures associated with Lennox-Gastaut syndrome was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 10) comparing a single dosage of TOPAMAX ® with placebo in patients 2 years of age and older (see Table 13).

Patients in Study 10 were permitted a maximum of two antiepileptic drugs (AEDs) in addition to TOPAMAX ® or placebo. Patients who were experiencing at least 60 seizures per month before study entry were stabilized on optimum dosages of their concomitant AEDs during a 4-week baseline phase. Following baseline, patients were randomly assigned to placebo or TOPAMAX ® in addition to their other AEDs. Active drug was titrated beginning at 1 mg/kg/day for a week; the dose was then increased to 3 mg/kg/day for one week, then to 6 mg/kg/day. After titration, patients entered an 8-week stabilization period.

The primary measures of effectiveness were the percent reduction in drop attacks and a parental global rating of seizure severity.

Table 12: TOPAMAX ® Dose Summary During the Stabilization Periods of Each of Six Double-Blind, Placebo-Controlled, Adjunctive Trials in Adults with Partial-Onset Seizures Dose-response studies were not conducted for other indications or pediatric partial-onset seizures.
Target TOPAMAX ® Dosage (mg/day)
Study Stabilization Dose Placebo Placebo dosages are given as the number of tablets. Placebo target dosages were as follows: Protocol 3 4 tablets/day; Protocols 1 and 4, 6 tablets/day; Protocols 5 and 6, 8 tablets/day; Protocol 2, 10 tablets/day. 200 400 600 800 1,000
2 N 42 42 40 41 -- --
Mean Dose 5.9 200 390 556 -- --
Median Dose 6.0 200 400 600 -- --
3 N 44 -- -- 40 45 40
Mean Dose 9.7 -- -- 544 739 796
Median Dose 10.0 -- -- 600 800 1,000
4 N 23 -- 19 -- -- --
Mean Dose 3.8 -- 395 -- -- --
Median Dose 4.0 -- 400 -- -- --
5 N 30 -- -- 28 -- --
Mean Dose 5.7 -- -- 522 -- --
Median Dose 6.0 -- -- 600 -- --
6 N 28 -- -- -- 25 --
Mean Dose 7.9 -- -- -- 568 --
Median Dose 8.0 -- -- -- 600 --
7 N 90 157 -- -- -- --
Mean Dose 8 200 -- -- -- --
Median Dose 8 200 -- -- -- --

In all adjunctive trials, the reduction in seizure rate from baseline during the entire double-blind phase was measured. The median percent reductions in seizure rates and the responder rates (fraction of patients with at least a 50% reduction) by treatment group for each study are shown below in Table 13. As described above, a global improvement in seizure severity was also assessed in the Lennox-Gastaut trial.

Table 13: Efficacy Results in Double-Blind, Placebo-Controlled, Adjunctive Epilepsy Trials
Target TOPAMAX Dosage (mg per day)
Study # # Placebo 200 400 600 800 1,000 ≈6mg/kg/day For Studies 8 and 9, specified target dosages (<9.3 mg/kg/day) were assigned based on subject's weight to approximate a dosage of 6mg/kg per day; these dosages corresponded to mg/day dosages of 125, 175, 225, and 400 mg/day
Comparisons with placebo: ap=0.080; bp ≤ 0.010; cp ≤ 0.001; dp ≤ 0.050; ep=0.065; fp ≤0.005; gp=0.071;
hMedian % reduction and % responders are reported for PGTC seizures;
iMedian % reduction and % responders for drop attacks, i.e., tonic or atonic seizures
jPercentage of subjects who were minimally, much, or very much improved from baseline.
Partial-Onset Seizures Studies in Adults
2 N 45 45 45 46 -- -- --
Median % Reduction 12 27 a 48 b 45 c -- -- --
% Responders 18 24 44 d 46 d -- -- --
3 N 47 -- -- 48 48 47 --
Median % Reduction 2 -- -- 41 c 41 c 36 c
% Responders 9 -- -- 40 c 41 c 36 d
4 N 24 -- 23 -- -- -- --
Median % Reduction 1 -- 41 e -- -- -- --
% Responders 8 -- 35 d -- -- -- --
5 N 30 -- -- 30 -- -- --
Median % Reduction -12 -- -- 46 f -- -- --
% Responders 10 -- -- 47 c -- -- --
6 N 28 -- -- -- 28 -- --